Oros System Research Articles

Polyvinyl acetate-based film coatings

Polyvinyl acetate-based colloidal aqueous polymer dispersion Kollicoat(®) SR 30 D results in coatings characterized by moderate swelling behaviour, lipophilicity, pH-independent permeability for actives and high flexibility to withstand mechanical stress and is therefore used for controlled release coating. The colloidal aqueous polymer dispersion of Kollicoat(®) SR 30 D can be easily processed due to an optimal low minimum film forming temperature (MFT) of 18 °C without plasticizer addition and a thermal after-treatment (curing) of coated pellets. The drug release from Kollicoat(®) SR 30 D coated pellets was almost pH independent. Drug release could be easily adjusted by coating level or addition of soluble pore forming polymers. Physically stable Kollicoat(®) SR 30 D dispersions were obtained with the water-soluble polymers Kollidon(®) 30 and Kollicoat(®) IR up to 50% w/w. The addition of only 10% w/w triethyl citrate as plasticizer improved the flexibility of the films significantly and allowed compaction of the pellets. The drug release was almost independent of the compression force and the pellet content of the tablets. The inclusion of various tableting excipients slightly affected the drug release, primarily because of a different disintegration rate of the tablets. A combination of Kollicoat(®) SR 30 D and Kollicoat(®) IR with higher coating levels>10 mg/cm(2) is a relatively new alternative to OROS system which does not require drilling.

OROS methylphenidate hydrochloride for adult patients with attention deficit/hyperactivity disorder

Introduction: Attention deficit/hyperactivity disorder (ADHD) is estimated to affect 4 – 5% of adults. Impairment across multiple domains of daily living can be mild to serious. OROS methylphenidate (MPH) was evaluated in two large adult clinical trials, and in 2008 it was approved in the USA to treat ADHD in adults aged up to 65 years.Areas covered: Products approved for adult ADHD; chemistry, pharmacodynamics, pharmacokinetics, metabolism, efficacy, safety, tolerability, abuse liability, regulatory affairs, and relative merits and limitations associated with OROS MPH; and complexities associated with diagnosis and treatment of ADHD are discussed in this review. The reader will gain an introduction to the epidemiology, features and special issues regarding clinical management of ADHD in adults. Key features and development of OROS MPH are presented, and unique characteristics of the delivery system and their implications for clinical use of the drug are discussed.Expert opinion: The OROS system delivers MPH in a highly consistent manner using osmotic pressure at a controlled rate over a 12-h duration of effect. Compared with immediate-release MPH, it provides a smoother pharmacokinetic curve, and it may show greater patient compliance, fewer missed doses and reduced abuse liability.

Relationship between systemic drug absorption and gastrointestinal transit after the simultaneous oral administration of carbamazepine as a controlled‐release system and as a suspension of 15N‐labelled drug to healthy volunteers.

1. Plasma drug concentrations after a single oral administration of a suspension of carbamazepine (CBZ) and a 20/200 CBZ Oros osmotic pump system were measured in eight healthy male volunteers. The oral suspension contained 100 mg CBZ labelled with the stable isotope nitrogen-15, whilst the Oros contained 200 mg unlabelled CBZ. Plasma concentrations of [15N]-CBZ and CBZ were measured simultaneously by gas chromatography-mass spectrometry. 2. The position of the CBZ Oros (labelled with indium-111) in the gastrointestinal tract was followed by gamma scintigraphy. Plasma drug concentrations after the two treatments were used to relate pharmacokinetic with transit data. 3. The Oros was taken after breakfast and gastric emptying occurred between 1.1- greater than h post-dosing (median, 5.3 h). Small intestinal transit times ranged from 1.5- greater than 3.6 h, with a median of 2.2 h. There were wide individual variations in colonic transit, and the total transit time ranged from 10-60 h (median, 22 h). 4. Relative systemic bioavailability of CBZ from the Oros was reduced compared with that from the suspension (mean dose normalised AUC ratio = 0.69 +/- 0.17; mean dose-normalised AUC ratio = 0.85 +/- 0.13, allowing for actual release from the Oros system). 5. The in vivo absorption of drug into the systemic circulation from the Oros was estimated using the Wagner-Nelson method. This showed that absorption of CBZ was rapid when the Oros was present in the stomach and small intestine, the rate being determined by the release of drug from the system.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of food on the bioavailability of metoprolol from an OROS system; a study in healthy volunteers

The influence of food intake on the bioavailability of metoprolol from an OROS system has been investigated. No significant difference was found between OROS administration to fasting subjects or after breakfast in any of the kinetic parameters (AUC, Cmax, tmax, C24 and lag time). Therefore, metoprolol OROS can be administered with breakfast.

A structured approach to the development of a controlledrelease drug delivery system for a β-adrenoceptor blocking drug

A structured approach to the development of a once-daily drug delivery system for the β-adrenergic receptor antagonist, metoprolol fumarate, is described. Performance attributes of the system were defined on the basis of the interrelationships between a relevant pharmacological property of the drug (attenuation in exercise heart rate), plasma drug concentrations after oral administration, and in vitro delivery rates for OROS systems. An analysis of exercise heart rate data suggested a therapeutic plasma concentration range of 45–150 ng/ml for this drug. Simulations based on a numerical convolution algorithm indicated that OROS itsystems with zero-order delivery rates of 11 mg/h or less should maintain plasma levels within the required range during multiple dosing. However, data in healthy volunteers showed that in vivo itabsorption is slightly slower than in vitro delivery and that an OROS system with a delivery rate of 14 mg/h should satisfy the requirements for a once-daily dosage form.

Relationship between the rate of appearance of oxprenolol in the systemic circulation and the location of an oxprenolol Oros 16/260 drug delivery system within the gastrointestinal tract as determined by scintigraphy.

1. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium-99m DTPA was followed by gamma scintigraphy, and the corresponding plasma drug concentration-time profiles after oral and i.v. administration were used to relate pharmacokinetic and transit data. 2. Gastric emptying time (0.8 +/- 0.4 h, mean +/- s.d.), and the time to arrival in the colon (3.8 +/- 0.7 h) were reasonably consistent after administration of the Oros system to fasted subjects, as were the calculated small intestine transit times (3.0 +/- 0.7 h). As expected there were wide individual variations in colonic transit, so that recorded values for total transit ranged from 6 to 32 h (median, 24.7 h). 3. Absorption of oxprenolol occurred throughout the GI tract including the colon. Plasma drug concentration-time profiles and input functions (calculated by deconvolution) could be related to transit behaviour and in vitro release. Inflexions in the calculated rate of drug input when the Oros system was located in the colon corresponded with periods of stagnation at the hepatic and splenic flexures in two subjects and the ileocaecal junction in two others. The mechanism of these changes is unclear.

Influence of food intake on plasma oxprenolol concentrations following oral administration of conventional and Oros preparations.

Plasma concentrations of oxprenolol have been measured in six healthy volunteers following single-dose oral administration of the drug in conventional and Oros dosage forms in fasting and postprandial states. After the Oros system, plasma concentrations reached peaks in most subjects at 3-8 h after dosing and were approximately 25% of those achieved with the conventional tablet. Plasma concentrations were well sustained for at least 24 h. A secondary peak occurred consistently at 12 h, possibly reflecting a transient change in clearance and/or distribution of the drug following the evening meal. With each formulation, plasma drug concentration profiles following administration in the fasting state did not differ significantly from those obtained when the drug was given postprandially. Drug absorption in vivo corresponded reasonably closely with in vitro drug release from the Oros system.

Oros controlled-release formulations of metoprolol: an approach to the development of a system for once daily administration.

A combined biopharmaceutical and haemodynamic approach to the development of a metoprolol Oros controlled-release delivery system for once daily administration is reported. Two studies, each involving 18 healthy volunteers, were performed in which twice daily administration of 100 mg conventional metoprolol tartrate tablets was compared with once daily administration of Oros systems containing 190 mg metoprolol fumarate but with different drug release rates. Plasma drug concentrations and beta-adrenoceptor blocking effects were measured over 24 h on days 1 and 5 of each treatment, and pre-dose in the interval between the main study days. The results of the first study with a 19 mg/h Oros system indicated that this rate was too rapid to provide the required response under steady-state dosing conditions. Theoretical calculations based on a one-compartment pharmacokinetic model and input functions for hypothetical Oros systems were then performed to define the optimal release rate for a once daily preparation. The results of the second study confirmed that a 14 mg/h system possessed the required characteristics in that it maintained more uniform beta-adrenoceptor blockade throughout 24 h, and produced pre-dosing plasma concentrations and haemodynamic effects which were identical to those for the conventional tablet twice daily regimen.

Reproducibility of oxprenolol plasma concentrations in young female volunteers following oral administration of an oxprenolol Oros dosage form.

Plasma oxprenolol concentrations were measured in six young healthy female volunteers after single oral dosing with a 16/260 oxprenolol Oros system on three separate occasions. Reproducibility was assessed by comparing individual plasma profiles, areas under the curve, peak concentrations and times to peak. Plasma concentration-time profiles were consistent with an extended duration of drug release from the Oros system. Individual and mean profiles on the three occasions were similar, and no significant differences in mean plasma levels, or derived pharmacokinetic parameters, were detected. The mean amount of drug in eight systems recovered from faeces corresponded to 11% of the dose. Individual amounts were related to the total transit time of the system through the body. The 16/260 Oros system functioned reproducibly within the gastrointestinal tract, and in vivo absorption mirrored in vitro drug release.

In vitro and in vivo deconvolution assessment of drug release kinetics from oxprenolol Oros preparations.

The relationship between in vitro and in vivo drug release from Oros systems has been examined by analysing plasma concentration data from two pharmacokinetic studies, using a numerical deconvolution technique. This method generates an input profile by comparing the response with that achieved following an instantaneous reference unit dose. The approach is conceptually simple and does not require compartmental pharmacokinetic modelling or curve fitting. In the analysis of the first study, the plasma profile following intravenous dosing was used as the reference function, allowing the combined release/absorption process to be calculated; for the second, an oral bolus was used, the result of the deconvolution therefore indicating the in vivo dissolution rate of the Oros systems. The in vivo release from Oros in most volunteers followed the same pattern as that measured in vitro; only after 6-8 h was the decline in the in vivo release rate somewhat greater than expected. In a few individuals the cumulative absorption profile reached an early plateau level which coincided, on some but not all occasions, with the premature excretion of the Oros system from the body. The amount of drug in recovered systems agreed reasonably with the prediction of the deconvolution analysis.

Pharmacokinetic investigation of the absorption of oxprenolol from Oros delivery systems in healthy volunteers: comparison of in vivo and in vitro drug release.

The absorption kinetics of oxprenolol have been investigated in eight healthy volunteers after single dosing with 16/260 Oros drug delivery systems. Oxprenolol disposition kinetics in individual subjects were estimated from intravenous dose data. Loo-Riegelman analysis of the plasma concentration data indicated an extended duration of drug absorption for the Oros system. Initially, the in vivo absorption rate was similar to the in vitro release rate but after 5-6 h it slowed perceptibly. However, at later times similar in vivo and in vitro rates were again observed. The absolute bioavailabilities for prototype and clinical trial systems were shown to be similar, at approximately 42%, and no significant differences in plasma profiles or pharmacokinetic constants were detected between the two Oros forms. A comparison of plasma concentration data in seven subjects who received the prototype system on two occasions in separate studies indicated a consistent level of drug absorption from this preparation. Approximately 10-15% of the administered dose was found in Oros systems recovered from faeces. The quantity of drug remaining was poorly correlated with the observed areas under the plasma concentration-time curve.

A multiple dose pharmacokinetic and pharmacodynamic evaluation of conventional and 19/285 Oros formulations of metoprolol in healthy volunteers.

Plasma metoprolol concentrations and haemodynamic effects have been measured in six healthy male volunteers during once daily dosing with a 19/285 Oros system and twice daily dosing with 100 mg conventional tablets, on two separate occasions. Plasma drug concentrations throughout the day varied less with the Oros than with the conventional tablet regimen. Predosing concentrations were also higher with Oros but areas under the curve, after correcting for the differences in dose, were similar for the two preparations. Inhibition of exercise tachycardia was drug concentration dependent and was smoothly controlled through the day only with the Oros preparation. Predosing effects at steady-state were also greater for the Oros regimen. The decline in mean blood pressure, however, showed the same daily pattern for both regimens, and no significant differences were detected between Oros and conventional tablet treatments. The smoothness of the plasma profiles after Oros confirmed the controlled-release performance of the system in vivo and indicates its potential in the treatment of angina, cardiac arrhythmias and wherever it is important not to jeopardize steady selective beta-adrenoceptor blockade.

Influence of food on the absorption of metoprolol administered as an Oros drug delivery system to man.

The influence of food on the release, absorption and metabolism of metoprolol has been studied after single administration of a 19/190 Oros system to eight healthy volunteers on four occasions, once after an overnight fast, and just before each of three daily meals (breakfast, lunch and dinner). The plasma concentration-time profiles under the four test conditions were virtually identical, and no statistically significant differences in mean areas under the curves between 0 and 32 h, peak concentrations, or times to peak, were detected. The absorption of metoprolol was unaffected by food intake, with 80-90% of the amount absorbed reaching the systemic circulation within 10 h. The ratios of areas under the curve for alpha-hydroxymetoprolol to its parent drug were in the same range for the four treatments, and similar to those reported after conventional tablets. The in vivo release and absorption of drug from the Oros system and its systemic availability, were not influenced by concomitant ingestion of food.

Osmotically controlled-delivery of metoprolol in man: in vivo performance of Oros systems with different durations of drug release.

In vivo absorption from 19/190 and 19/285 metoprolol Oros drug delivery systems has been assessed by measuring plasma drug concentrations after single administration of the systems to six healthy volunteers. The initial in vitro release rate for both Oros preparations was 19 mg/h but they contained 190 or 285 mg of metoprolol fumarate. The plasma concentration-time profiles for both Oros dosage forms were consistent with an extended duration of release and absorption from the gastrointestinal tract. Analysis of the plasma level data indicated that the rate and duration of in vivo absorption closely mirrored the in vitro release behaviour of the 19/190 and 19/285 systems, but the in vivo profiles showed a 1-2 h initial delay. The administration of the 19/190 system on two occasions to the same six volunteers indicated that in vivo release of drug from this Oros preparation was reproducible.

Adherence of various oral dosage forms to the esophagus

The potential for various tablets and capsules to adhere to the esophagus or gastrointestinal tract was evaluated in the isolated dog and swine esophagus, using a modification of the procedure of Marvola et al. (1982), in which the swine esophagus was used. The utility of the dog model was demonstrated by showing that comparable adherence values were obtained when the same products were tested in both dog and swine esophagus, and by confirming in the dog model the main findings of Marvola et al. that: (1) force of adherence to the esophagus depends on the type of product, ranking from the greatest to least adherence—hard gelatin capsules, film-coated tablets, uncoated tablets, sugar-coated tablets; (2) for a given product type, adherence increases in proportion to size; and (3) increasing the amount of fluid in the esophagus decreases adherence. The adherence forces of OROS osmotic systems were the lowest of the film-coated products tested. The adherence force of the OROS system lacking an overcoat of hydroxypropyl methyl cellulose (HPMC) was comparable to the negative control salt tablet, while that of the OROS system containing an HPMC overcoat was slightly higher, but still only about one-quarter of that of the commercial gelatin capsules tested. Additionally, the adherence force of the HPMC-coated OROS system was reduced by increasing fluid in the esophagus, simulating the ingestion of a small